Discovery of 5‑{4-[(7-Ethyl-6-oxo‑5,6-dihydro‑1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}‑N‑methylpyridine-2-carboxamide (AZD5305): A
PARP1–DNA Trapper with High Selectivity for PARP1 over PARP2
and Other PARPs
Posted on 2021-09-27 - 20:05
Poly-ADP-ribose-polymerase (PARP)
inhibitors have achieved regulatory
approval in oncology for homologous recombination repair deficient
tumors including BRCA mutation. However, some have failed in combination
with first-line chemotherapies, usually due to overlapping hematological
toxicities. Currently approved PARP inhibitors lack selectivity for
PARP1 over PARP2 and some other 16 PARP family members, and we hypothesized
that this could contribute to toxicity. Recent literature has demonstrated
that PARP1 inhibition and PARP1–DNA trapping are key for driving
efficacy in a BRCA mutant background. Herein, we describe the structure-
and property-based design of 25 (AZD5305), a potent and
selective PARP1 inhibitor and PARP1–DNA trapper with excellent
in vivo efficacy in a BRCA mutant HBCx-17 PDX model. Compound 25 is highly selective for PARP1 over other PARP family members,
with good secondary pharmacology and physicochemical properties and
excellent pharmacokinetics in preclinical species, with reduced effects
on human bone marrow progenitor cells in vitro.
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Johannes, Jeffrey W.; Balazs, Amber; Barratt, Derek; Bista, Michal; Chuba, Matthew D.; Cosulich, Sabina; et al. (2021). Discovery of 5‑{4-[(7-Ethyl-6-oxo‑5,6-dihydro‑1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}‑N‑methylpyridine-2-carboxamide (AZD5305): A
PARP1–DNA Trapper with High Selectivity for PARP1 over PARP2
and Other PARPs. ACS Publications. Collection. https://doi.org/10.1021/acs.jmedchem.1c01012